The identification of tetrahydrocannabinol (THC) as the active principle of marijuana (Cannabis sativa) prompted medicinal chemists to develop numerous cannabinoid analogs (reviewed by Barth, in Exp. Opin. Ther. Patents 8:301–313, 1998). These novel compounds were designed to exhibit the beneficial properties of THC without the accompanying psychotropic effects, which limit its therapeutic utility. Potential therapeutic applications have classically included known attributes of marijuana itself such as anti-emesis, analgesia, antiglaucoma and appetite stimulation. More recently recognized roles for non-psychotropic cannabinoids are as neuroprotective and anti-inflammatory agents.
Neuroprotective Activity
Chronic degenerative changes, as well as delayed or secondary neuronal damage following direct injury to the central nervous system (CNS), may result from pathologic changes in the brain's endogenous neurochemical systems. Although the precise mechanisms mediating secondary damage are poorly understood, post-traumatic neurochemical changes may include overactivation of neurotransmitter release or re-uptake, changes in presynaptic or postsynaptic receptor binding, or the pathologic release or synthesis of endogenous factors. The identification and characterization of these factors and of the timing of the neurochemical cascade after CNS injury provides a window of opportunity for treatment with pharmacologic agents that modify synthesis, release, receptor binding, or physiologic activity with subsequent attenuation of neuronal damage and improvement in outcome. A number of studies have suggested that modification of post-injury events through pharmacologic intervention can promote functional recovery in both a variety of animal models and clinical CNS injury. Pharmacologic manipulation of endogenous systems by such diverse pharmacologic agents as anticholinergics, excitatory amino acid antagonists, including specifically NMDA receptor antagonists, endogenous opioid antagonists, catecholamines, serotonin antagonists, modulators of arachidonic acid, antioxidants and free radical scavengers, steroid and lipid peroxidation inhibitors, platelet activating factor antagonists, anion exchange inhibitors, magnesium, gangliosides, and calcium channel antagonists have all been suggested to potentially improve functional outcome after brain injury (Mcintosh, J. Neurotrauma 10:215–243, 1993).
The pathogenesis of a diverse group of neurological disorders has been linked to excessive activation of excitatory amino acid receptors. These disorders include epilepsy, focal and global ischemia, CNS trauma, and various forms of neurodegeneration including Huntington's chorea, Parkinson's disease and Alzheimer's disease. There has been extensive effort invested in the development of excitatory amino acid receptor antagonists as therapeutic agents (Rogawski, Trends in Pharmacol. Sci. 14:325–331,1993 and Danbolt, Progress in Neurobiology 65:1–105, 2001).
Since no proven effective therapy for neuronal injury, or degeneration, is yet known, and, for example, stroke alone is one of the leading causes of death in many countries, the importance of finding such therapeutic NMDA antagonists is self-evident. It will be important to determine whether certain NMDA receptor antagonists are more effective—or have fewer side effects—than others in specific disease states.
Some of the compounds of general Formula (I) are disclosed in U.S. Pat. Nos. 4,179,517 and 4,876,276. As disclosed in said U.S. patents, these essentially pure synthetic (+)-(3S,4S)-THC derivatives and analogues are devoid of any undesired cannabimimetic psychotropic side effects. These known compounds have been described as having analgesic, antiemetic and antiglaucoma activity.
A particular compound of interest of Formula I, namely 1,1 dimethyl heptyl-(3S,4S)-7-hydroxy-Δ6-tetrahydrocannabinol, is disclosed in U.S. Pat. No. 4,876,276, and denoted therein as HU-211, and subsequently assigned the trivial chemical name dexanabinol. HU-211 was unexpectedly discovered to possess neuroprotective attributes, which may be ascribed to its activity as a non-competitive antagonist at the NMDA receptor, as disclosed in U.S. Pat. Nos. 5,284,867 and 5,521,215. Certain ester derivatives of dexanabinol are also active in neuroprotection, as disclosed in U.S. Pat. No. 6,096,740 as are the carboxylic acid derivatives of HU-211 as disclosed in U.S. Pat. Nos. 5,538,993 and 5,635,530.
Anti-Inflammatory Activity
Besides NMDA receptor blocking activity, dexanabinol and its ester derivatives were further shown to possess anti-oxidative and anti-inflammatory properties, which may contribute to their efficacy in preventing or alleviating ischemic damage to tissues.
In addition, derivatives of HU-211 were surprisingly shown to possess immunomodulatory potential due to their ability to inhibit Tumor Necrosis Factor alpha as disclosed in U.S. Pat. No. 5,932,610.
Certain natural non-psychotropic cannabinoids, including the derivative cannabidiol, have been found to have antioxidant properties unrelated to NMDA receptor antagonism as disclosed in WO 99/53917.
Endogenous ligands of the cannabinoid receptors (Mechoulam, et al., Endocannabinoids, Eur. J. Pharmacol. 359:1–18,1998) have been identified as being arachidonyl derivatives including 2-arachidonyl glycerol, and arachidonyl-ethanolamide (anandamide). Thus, these endocannabinoids are chemically related to certain metabolites in the arachidonic acid pathway.
A family of compounds known to exhibit inflammatory properties is the prostaglandins (PG). Prostaglandins are arachidonic acid metabolites, produced by the action of cyclooxygenase (COX) also known as PGH synthase. The first step in the production of prostaglandins from arachidonic acid (AA) is the bis-oxygenation of arachidonic acid to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. COX catalyzes both of these reactions. Two isoforms of COX have been identified, COX-1 and COX-2. Although both perform the same catalytic activity they differ in tissue distribution, regulation and expression (Williams and DuBois Am J Physiol. 270:G393–400, 1996).
COX-1 is constitutively expressed and appears to be involved in the physiological production of PGs. Although COX-2 has a normal pattern of expression in some body tissues it is primarily an inducible form that is expressed upon prolonged exposure to chemical mediators including cytokines and endotoxin (reviewed in Golden and Abramson, Selective Cyclooxygenase-2 inhibitors, Osteoarthritis 25:359–378,1999) Pain and inflammation in certain pathological processes are mediated by the COX-2 dependent production of PGE2. There is considerable interest in developing anti-inflammatory therapeutic strategies that block the activity of COX-2 and the biosynthesis of PGE2 resulting from activation of the Arachidonic acid/prostaglandin (AA/PG) biosynthetic pathway.
Attenuation of COX-2 activity is correlated with a reduction in pain, inflammation and fever. For example, the NSAIDs (non-steroidal anti-inflammatory drugs) act by blocking the COX enzymes. A reduction of 40–50% in the colon cancer rate among cardiovascular patients in the US who are given prophylactic doses of aspirin (a common NSAID) was also shown to be related to a decrease in COX-2 expression (Smalley and DuBois, Adv Pharmacol 39:1–20, 1997).
Therapeutic strategies that target this pathway are sought to prevent and treat a variety of diseases and symptoms such as neuronal degeneration in diseases as Alzheimer's disease or Parkinson's disease, neuronal trauma associated with seizures, brain or CNS damage, inflammation associated with rheumatoid arthritis; bone resorption and colonic polyposis and colorectal cancer (reviewed in Lipsky, J Rheumatol 26: Suppl 56:25–30, 1999). U.S. Pat. No. 5,840,746 teaches the method of treating neurodegenerative disease by administering non-steroidal COX-2 inhibitors that specifically bind to COX-2. Inflammation has also been implicated as part of the pathogenesis in myocardial infarction, atheroma, unstable angina and other cardiac disorders (Ross, New England J Med 340:115–126, 1999).
There is an unmet need for and it would be advantageous to have novel non-psychotropic cannabinoid compounds that exert their effects via a plurality of mechanisms. Ideally, in addition to having said analgesic, antiemetic and anti-glaucoma activities, they would also be effective against the diseases and conditions mentioned above. The mechanisms invoked in these pleitropic effects include their action as excitatory amino acid receptor blockers, for example NMDA-receptor or glutamate-blockers or interaction with the glycine receptor, or as inhibitors of either the oxidative, cytokine, nitric oxide or AA/PG pathways, including the cyclooxygenase and lipoxygenase and are effective in the alleviation and treatment of many of the abnormal states involving said neurotransmitter or pathway mediated toxicity. The present invention now provides such compounds.